Primary Outcome

Death from any cause or requirement of new intensive respiratory support (invasive or non-invasive ventilation) or vasopressor/inotropic support in the 28 days after randomisation.

This document reports on the analysis of the primary outcome for ASCOT.

Author

James Totterdell

Published

July 26, 2023

Primary Outcome Definition

The primary outcome is a composite of death, need for new respiratory support, or vasopressor/inotropic support. From the protocol:

Death from any cause or requirement of new intensive respiratory support (invasive or non-invasive ventilation) or vasopressor/inotropic support in the 28 days after randomisation. This includes any participant who receives non-invasive mechanical ventilation (either CPAP or BIPAP, apart from the below considerations) any time after enrolment even if not transferred to ICU. It does NOT include the use of humidified high-flow nasal prong oxygen.

Participants on pre-existing home BiPAP or CPAP will not be considered to have met the primary outcome unless they have either:

  • required invasive mechanical ventilation (i.e. intubation), or
  • graduated from CPAP only whilst asleep to BiPAP at any time, or
  • graduated from BiPAP only whilst asleep to BiPAP for >12 hours/day, or
  • died by day 28

There may be cases where a patient has been assessed as requiring intensive respiratory support (invasive or non-invasive ventilation) or vasopressor/inotropic support, but the patient or family declined treatment and the patient was discharged home. If attempts to obtain 28-day data are unsuccessful or not possible, and the investigator had deemed at the time of discharge that the patient would be highly likely to die within 28 days from randomisation, these participants will be deemed to have met the primary outcome.

Derivation of the Outcome

Derivation of the outcome requires checking of the daily, discharge, and day 28 data extracts. On the daily data, there is a variable DD_PrimaryEndpointReachedToday however this was coded incorrectly in the original database and therefore fails to capture some participants. Additionally, given the composite nature of the outcome it is useful to check all components individually as well as the composite outcome. Therefore, this variable is not used in the derivation, but is included as a cross-check.

Below, each component is summarised in aggregate for the FAS-ITT set.

Day 28 mortality

Antiviral
Anticoagulation
Outcome Breakdown A0 A1 A2 C0 C1 C2 C3 C4 Overall
Mortality
Alive at day 28 1364 (95.2) 73 (100.0) 82 (100.0) 32 (100.0) 579 (94.9) 593 (96.7) 271 (95.8) 44 (88.0) 1519 (95.7)
Death within 28 days Total 50 (3.5) 0 (0.0) 0 (0.0) 0 (0.0) 19 (3.1) 15 (2.4) 10 (3.5) 6 (12.0) 50 (3.1)
Death within 28 days Prior to discharge 40 (2.8) 0 (0.0) 0 (0.0) 0 (0.0) 15 (2.5) 11 (1.8) 10 (3.5) 4 (8.0) 40 (2.5)
Death within 28 days Post-discharge 10 (0.7) 0 (0.0) 0 (0.0) 0 (0.0) 4 (0.7) 4 (0.7) 0 (0.0) 2 (4.0) 10 (0.6)
Unknown 19 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 12 (2.0) 5 (0.8) 2 (0.7) 0 (0.0) 19 (1.2)
Total 1433 (100.0) 73 (100.0) 82 (100.0) 32 (100.0) 610 (100.0) 613 (100.0) 283 (100.0) 50 (100.0) 1588 (100.0)
Table 1: 28-day mortality by domain intervention and overall.

Vasopressor/inotropic requirement

Antiviral
Anticoagulation
Outcome Breakdown A0 A1 A2 C0 C1 C2 C3 C4 Overall
Vasopressor/inotropes
Not required 1391 (97.1) 71 (97.3) 81 (98.8) 31 (96.9) 592 (97.0) 599 (97.7) 273 (96.5) 48 (96.0) 1543 (97.2)
Use within 28 days Total 18 (1.3) 2 (2.7) 1 (1.2) 1 (3.1) 6 (1.0) 6 (1.0) 6 (2.1) 2 (4.0) 21 (1.3)
Use within 28 days Prior to discharge 17 (1.2) 2 (2.7) 1 (1.2) 1 (3.1) 5 (0.8) 6 (1.0) 6 (2.1) 2 (4.0) 20 (1.3)
Use within 28 days Post-discharge 3 (0.2) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.3) 0 (0.0) 0 (0.0) 1 (2.0) 3 (0.2)
Unknown 24 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 12 (2.0) 8 (1.3) 4 (1.4) 0 (0.0) 24 (1.5)
Total 1433 (100.0) 73 (100.0) 82 (100.0) 32 (100.0) 610 (100.0) 613 (100.0) 283 (100.0) 50 (100.0) 1588 (100.0)
Table 2: 28-day vasopressor/inotrope use by domain intervention and overall.

New intensive respiratory support

Antiviral
Anticoagulation
Outcome Breakdown A0 A1 A2 C0 C1 C2 C3 C4 Overall
Ventilation
Not required 1339 (93.4) 65 (89.0) 78 (95.1) 28 (87.5) 564 (92.5) 584 (95.3) 263 (92.9) 43 (86.0) 1482 (93.3)
Use within 28 days Total 76 (5.3) 8 (11.0) 4 (4.9) 4 (12.5) 35 (5.7) 24 (3.9) 18 (6.4) 7 (14.0) 88 (5.5)
Use within 28 days Prior to discharge 58 (4.0) 8 (11.0) 4 (4.9) 4 (12.5) 29 (4.8) 19 (3.1) 13 (4.6) 5 (10.0) 70 (4.4)
Use within 28 days Post-discharge 18 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 6 (1.0) 5 (0.8) 5 (1.8) 2 (4.0) 18 (1.1)
Unknown 18 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 11 (1.8) 5 (0.8) 2 (0.7) 0 (0.0) 18 (1.1)
Total 1433 (100.0) 73 (100.0) 82 (100.0) 32 (100.0) 610 (100.0) 613 (100.0) 283 (100.0) 50 (100.0) 1588 (100.0)
Table 3: 28-day new intensive respiratory support by domain intervention and overall.

Primary Outcome Composite

Antiviral
Anticoagulation
Outcome Breakdown A0 A1 A2 C0 C1 C2 C3 C4 Overall
Primary outcome
No 1331 (92.9) 65 (89.0) 78 (95.1) 28 (87.5) 563 (92.3) 581 (94.8) 259 (91.5) 43 (86.0) 1474 (92.8)
Yes 79 (5.5) 8 (11.0) 4 (4.9) 4 (12.5) 35 (5.7) 25 (4.1) 20 (7.1) 7 (14.0) 91 (5.7)
Unknown Total 23 (1.6) 0 (0.0) 0 (0.0) 0 (0.0) 12 (2.0) 7 (1.1) 4 (1.4) 0 (0.0) 23 (1.4)
Unknown Day 28 status 18 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 11 (1.8) 5 (0.8) 2 (0.7) 0 (0.0) 18 (1.1)
Unknown Vasopressor/inotropes 5 (0.3) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.2) 2 (0.3) 2 (0.7) 0 (0.0) 5 (0.3)
Total 1433 (100.0) 73 (100.0) 82 (100.0) 32 (100.0) 610 (100.0) 613 (100.0) 283 (100.0) 50 (100.0) 1588 (100.0)
Table 4: Composite primary endpoint breakdown - overall.
Anticoagulation
Outcome Breakdown Not
randomised
(n = 32)
Low
dose
(n = 610)
Intermediate
dose
(n = 613)
Low dose
with aspirin
(n = 283)
Therapeutic
dose
(n = 50)
Overall

(n = 1588)
Primary outcome
No 28 (87.5) 563 (92.3) 581 (94.8) 259 (91.5) 43 (86.0) 1474 (92.8)
Yes 4 (12.5) 35 (5.7) 25 (4.1) 20 (7.1) 7 (14.0) 91 (5.7)
Unknown Total 0 (0.0) 12 (2.0) 7 (1.1) 4 (1.4) 0 (0.0) 23 (1.4)
Unknown Day 28 status 0 (0.0) 11 (1.8) 5 (0.8) 2 (0.7) 0 (0.0) 18 (1.1)
Unknown Vasopressor/inotropes 0 (0.0) 1 (0.2) 2 (0.3) 2 (0.7) 0 (0.0) 5 (0.3)
Total 32 (100.0) 610 (100.0) 613 (100.0) 283 (100.0) 50 (100.0) 1588 (100.0)
Mortality
Alive at day 28 32 (100.0) 579 (94.9) 593 (96.7) 271 (95.8) 44 (88.0) 1519 (95.7)
Death within 28 days Total 0 (0.0) 19 (3.1) 15 (2.4) 10 (3.5) 6 (12.0) 50 (3.1)
Death within 28 days Prior to discharge 0 (0.0) 15 (2.5) 11 (1.8) 10 (3.5) 4 (8.0) 40 (2.5)
Death within 28 days Post-discharge 0 (0.0) 4 (0.7) 4 (0.7) 0 (0.0) 2 (4.0) 10 (0.6)
Unknown 0 (0.0) 12 (2.0) 5 (0.8) 2 (0.7) 0 (0.0) 19 (1.2)
Total 32 (100.0) 610 (100.0) 613 (100.0) 283 (100.0) 50 (100.0) 1588 (100.0)
Vasopressor/inotropes
Not required 31 (96.9) 592 (97.0) 599 (97.7) 273 (96.5) 48 (96.0) 1543 (97.2)
Use within 28 days Total 1 (3.1) 6 (1.0) 6 (1.0) 6 (2.1) 2 (4.0) 21 (1.3)
Use within 28 days Prior to discharge 1 (3.1) 5 (0.8) 6 (1.0) 6 (2.1) 2 (4.0) 20 (1.3)
Use within 28 days Post-discharge 0 (0.0) 2 (0.3) 0 (0.0) 0 (0.0) 1 (2.0) 3 (0.2)
Unknown 0 (0.0) 12 (2.0) 8 (1.3) 4 (1.4) 0 (0.0) 24 (1.5)
Total 32 (100.0) 610 (100.0) 613 (100.0) 283 (100.0) 50 (100.0) 1588 (100.0)
Ventilation
Not required 28 (87.5) 564 (92.5) 584 (95.3) 263 (92.9) 43 (86.0) 1482 (93.3)
Use within 28 days Total 4 (12.5) 35 (5.7) 24 (3.9) 18 (6.4) 7 (14.0) 88 (5.5)
Use within 28 days Prior to discharge 4 (12.5) 29 (4.8) 19 (3.1) 13 (4.6) 5 (10.0) 70 (4.4)
Use within 28 days Post-discharge 0 (0.0) 6 (1.0) 5 (0.8) 5 (1.8) 2 (4.0) 18 (1.1)
Unknown 0 (0.0) 11 (1.8) 5 (0.8) 2 (0.7) 0 (0.0) 18 (1.1)
Total 32 (100.0) 610 (100.0) 613 (100.0) 283 (100.0) 50 (100.0) 1588 (100.0)
Table 5: Composite primary endpoint breakdown for anticoagulation domain.
Antiviral
Outcome Breakdown Not randomised
to antiviral
(n = 1433)
Standard
of care
(n = 73)
Nafamostat

(n = 82)
Overall

(n = 1588)
Primary outcome
No 1331 (92.9) 65 (89.0) 78 (95.1) 1474 (92.8)
Yes 79 (5.5) 8 (11.0) 4 (4.9) 91 (5.7)
Unknown Total 23 (1.6) 0 (0.0) 0 (0.0) 23 (1.4)
Unknown Day 28 status 18 (1.3) 0 (0.0) 0 (0.0) 18 (1.1)
Unknown Vasopressor/inotropes 5 (0.3) 0 (0.0) 0 (0.0) 5 (0.3)
Total 1433 (100.0) 73 (100.0) 82 (100.0) 1588 (100.0)
Mortality
Alive at day 28 1364 (95.2) 73 (100.0) 82 (100.0) 1519 (95.7)
Death within 28 days Total 50 (3.5) 0 (0.0) 0 (0.0) 50 (3.1)
Death within 28 days Prior to discharge 40 (2.8) 0 (0.0) 0 (0.0) 40 (2.5)
Death within 28 days Post-discharge 10 (0.7) 0 (0.0) 0 (0.0) 10 (0.6)
Unknown 19 (1.3) 0 (0.0) 0 (0.0) 19 (1.2)
Total 1433 (100.0) 73 (100.0) 82 (100.0) 1588 (100.0)
Vasopressor/inotropes
Not required 1391 (97.1) 71 (97.3) 81 (98.8) 1543 (97.2)
Use within 28 days Total 18 (1.3) 2 (2.7) 1 (1.2) 21 (1.3)
Use within 28 days Prior to discharge 17 (1.2) 2 (2.7) 1 (1.2) 20 (1.3)
Use within 28 days Post-discharge 3 (0.2) 0 (0.0) 0 (0.0) 3 (0.2)
Unknown 24 (1.7) 0 (0.0) 0 (0.0) 24 (1.5)
Total 1433 (100.0) 73 (100.0) 82 (100.0) 1588 (100.0)
Ventilation
Not required 1339 (93.4) 65 (89.0) 78 (95.1) 1482 (93.3)
Use within 28 days Total 76 (5.3) 8 (11.0) 4 (4.9) 88 (5.5)
Use within 28 days Prior to discharge 58 (4.0) 8 (11.0) 4 (4.9) 70 (4.4)
Use within 28 days Post-discharge 18 (1.3) 0 (0.0) 0 (0.0) 18 (1.1)
Unknown 18 (1.3) 0 (0.0) 0 (0.0) 18 (1.1)
Total 1433 (100.0) 73 (100.0) 82 (100.0) 1588 (100.0)
Table 6: Composite primary endpoint breakdown for antiviral domain.

Summarise Primary Outcome

n (\%) Low
dose
Intermediate
dose
Low dose
with aspirin
Therapeutic
dose
Overall
Randomised 610 613 283 50 1556
Outcome missing 12 (2.0) 7 (1.1) 4 (1.4) 0 (0.0) 23 (1.5)
Outcome observed 598 (98.0) 606 (98.9) 279 (98.6) 50 (100.0) 1533 (98.5)
Met primary outcome 35 (5.9) 25 (4.1) 20 (7.2) 7 (14.0) 87 (5.7)
Table 7: Primary outcome by anti-coagulation intervention.
n (\%) Standard
of care
Nafamostat
Overall
Randomised 73 82 155
Outcome missing 0 (0.0) 0 (0.0) 0 (0.0)
Outcome observed 73 (100.0) 82 (100.0) 155 (100.0)
Met primary outcome 8 (11.0) 4 (4.9) 12 (7.7)
Table 8: Primary outcome by anti-viral intervention.

Descriptive Analyses

By Interim Analysis

Outcome \makecell[c]{Not\\randomised C} Low Intermediate \makecell[c]{Low with\\aspirin} Therapeutic
Overall (n = 1588)
Randomised 32 610 613 283 50
Known 32 (100) 598 (98) 606 (99) 279 (99) 50 (100)
Met primary outcome 4 (12) 35 (6) 25 (4) 20 (7) 7 (14)
Death 0 (0) 19 (3) 15 (2) 10 (4) 6 (12)
Vasopressor/inotropic support 1 (3) 6 (1) 6 (1) 6 (2) 2 (4)
Intensive respiratory support 4 (12) 35 (6) 24 (4) 18 (6) 7 (14)
Interim 1 (n = 685)
Randomised - 234 226 225 -
Known - 227 (97) 222 (98) 222 (99) -
Met primary outcome - 22 (10) 15 (7) 19 (9) -
Death - 13 (6) 11 (5) 9 (4) -
Vasopressor/inotropic support - 2 (1) 3 (1) 6 (3) -
Intensive respiratory support - 22 (10) 15 (7) 17 (8) -
Interim 2 (n = 259)
Randomised 13 90 98 58 -
Known 13 (100) 90 (100) 98 (100) 57 (98) -
Met primary outcome 0 (0) 2 (2) 3 (3) 1 (2) -
Death 0 (0) 1 (1) 3 (3) 1 (2) -
Vasopressor/inotropic support 0 (0) 1 (1) 0 (0) 0 (0) -
Intensive respiratory support 0 (0) 2 (2) 3 (3) 1 (2) -
Interim 3 (n = 392)
Randomised 8 177 172 - 35
Known 8 (100) 175 (99) 171 (99) - 35 (100)
Met primary outcome 3 (38) 8 (5) 4 (2) - 6 (17)
Death 0 (0) 4 (2) 0 (0) - 5 (14)
Vasopressor/inotropic support 0 (0) 3 (2) 2 (1) - 2 (6)
Intensive respiratory support 3 (38) 8 (5) 4 (2) - 6 (17)
Interim 4 (n = 237)
Randomised 3 108 112 - 14
Known 3 (100) 105 (97) 111 (99) - 14 (100)
Met primary outcome 1 (33) 3 (3) 3 (3) - 1 (7)
Death 0 (0) 1 (1) 1 (1) - 1 (7)
Vasopressor/inotropic support 1 (33) 0 (0) 1 (1) - 0 (0)
Intensive respiratory support 1 (33) 3 (3) 2 (2) - 1 (7)
Interim 5 (n = 15)
Randomised 8 1 5 - 1
Known 8 (100) 1 (100) 4 (80) - 1 (100)
Met primary outcome 0 (0) 0 (0) 0 (0) - 0 (0)
Death 0 (0) 0 (0) 0 (0) - 0 (0)
Vasopressor/inotropic support 0 (0) 0 (0) 0 (0) - 0 (0)
Intensive respiratory support 0 (0) 0 (0) 0 (0) - 0 (0)
Outcome \makecell[c]{Not\\randomised A} SoC Nafamostat
Overall (n = 1588)
Randomised 1433 73 82
Known 1410 (98) 73 (100) 82 (100)
Met primary outcome 79 (6) 8 (11) 4 (5)
Death 50 (4) 0 (0) 0 (0)
Vasopressor/inotropic support 18 (1) 2 (3) 1 (1)
Intensive respiratory support 76 (5) 8 (11) 4 (5)
Interim 1 (n = 685)
Randomised 683 - 2
Known 669 (98) - 2 (100)
Met primary outcome 56 (8) - 0 (0)
Death 33 (5) - 0 (0)
Vasopressor/inotropic support 11 (2) - 0 (0)
Intensive respiratory support 54 (8) - 0 (0)
Interim 2 (n = 259)
Randomised 202 31 26
Known 201 (100) 31 (100) 26 (100)
Met primary outcome 6 (3) 0 (0) 0 (0)
Death 5 (2) 0 (0) 0 (0)
Vasopressor/inotropic support 1 (0) 0 (0) 0 (0)
Intensive respiratory support 6 (3) 0 (0) 0 (0)
Interim 3 (n = 392)
Randomised 326 29 37
Known 323 (99) 29 (100) 37 (100)
Met primary outcome 12 (4) 7 (24) 2 (5)
Death 9 (3) 0 (0) 0 (0)
Vasopressor/inotropic support 5 (2) 2 (7) 0 (0)
Intensive respiratory support 12 (4) 7 (24) 2 (5)
Interim 4 (n = 237)
Randomised 220 6 11
Known 216 (98) 6 (100) 11 (100)
Met primary outcome 5 (2) 1 (17) 2 (18)
Death 3 (1) 0 (0) 0 (0)
Vasopressor/inotropic support 1 (0) 0 (0) 1 (9)
Intensive respiratory support 4 (2) 1 (17) 2 (18)
Interim 5 (n = 15)
Randomised 2 7 6
Known 1 (50) 7 (100) 6 (100)
Met primary outcome 0 (0) 0 (0) 0 (0)
Death 0 (0) 0 (0) 0 (0)
Vasopressor/inotropic support 0 (0) 0 (0) 0 (0)
Intensive respiratory support 0 (0) 0 (0) 0 (0)
Domain A
Domain C
Outcome \makecell[c]{Not\\randomised A} SoC Nafamostat \makecell[c]{Not\\randomised C} Low Intermediate \makecell[c]{Low with\\aspirin} Therapeutic
Overall (n = 1588)
Randomised 1433 73 82 32 610 613 283 50
Known 1410 (98) 73 (100) 82 (100) 32 (100) 598 (98) 606 (99) 279 (99) 50 (100)
Met primary outcome 79 (6) 8 (11) 4 (5) 4 (12) 35 (6) 25 (4) 20 (7) 7 (14)
Death 50 (4) 0 (0) 0 (0) 0 (0) 19 (3) 15 (2) 10 (4) 6 (12)
Vasopressor/inotropic support 18 (1) 2 (3) 1 (1) 1 (3) 6 (1) 6 (1) 6 (2) 2 (4)
Intensive respiratory support 76 (5) 8 (11) 4 (5) 4 (12) 35 (6) 24 (4) 18 (6) 7 (14)
Interim 1 (n = 685)
Randomised 683 - 2 - 234 226 225 -
Known 669 (98) - 2 (100) - 227 (97) 222 (98) 222 (99) -
Met primary outcome 56 (8) - 0 (0) - 22 (10) 15 (7) 19 (9) -
Death 33 (5) - 0 (0) - 13 (6) 11 (5) 9 (4) -
Vasopressor/inotropic support 11 (2) - 0 (0) - 2 (1) 3 (1) 6 (3) -
Intensive respiratory support 54 (8) - 0 (0) - 22 (10) 15 (7) 17 (8) -
Interim 2 (n = 259)
Randomised 202 31 26 13 90 98 58 -
Known 201 (100) 31 (100) 26 (100) 13 (100) 90 (100) 98 (100) 57 (98) -
Met primary outcome 6 (3) 0 (0) 0 (0) 0 (0) 2 (2) 3 (3) 1 (2) -
Death 5 (2) 0 (0) 0 (0) 0 (0) 1 (1) 3 (3) 1 (2) -
Vasopressor/inotropic support 1 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) -
Intensive respiratory support 6 (3) 0 (0) 0 (0) 0 (0) 2 (2) 3 (3) 1 (2) -
Interim 3 (n = 392)
Randomised 326 29 37 8 177 172 - 35
Known 323 (99) 29 (100) 37 (100) 8 (100) 175 (99) 171 (99) - 35 (100)
Met primary outcome 12 (4) 7 (24) 2 (5) 3 (38) 8 (5) 4 (2) - 6 (17)
Death 9 (3) 0 (0) 0 (0) 0 (0) 4 (2) 0 (0) - 5 (14)
Vasopressor/inotropic support 5 (2) 2 (7) 0 (0) 0 (0) 3 (2) 2 (1) - 2 (6)
Intensive respiratory support 12 (4) 7 (24) 2 (5) 3 (38) 8 (5) 4 (2) - 6 (17)
Interim 4 (n = 237)
Randomised 220 6 11 3 108 112 - 14
Known 216 (98) 6 (100) 11 (100) 3 (100) 105 (97) 111 (99) - 14 (100)
Met primary outcome 5 (2) 1 (17) 2 (18) 1 (33) 3 (3) 3 (3) - 1 (7)
Death 3 (1) 0 (0) 0 (0) 0 (0) 1 (1) 1 (1) - 1 (7)
Vasopressor/inotropic support 1 (0) 0 (0) 1 (9) 1 (33) 0 (0) 1 (1) - 0 (0)
Intensive respiratory support 4 (2) 1 (17) 2 (18) 1 (33) 3 (3) 2 (2) - 1 (7)
Interim 5 (n = 15)
Randomised 2 7 6 8 1 5 - 1
Known 1 (50) 7 (100) 6 (100) 8 (100) 1 (100) 4 (80) - 1 (100)
Met primary outcome 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) - 0 (0)
Death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) - 0 (0)
Vasopressor/inotropic support 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) - 0 (0)
Intensive respiratory support 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) - 0 (0)

Intervention

The following presents the primary outcome rate by antiviral intervention

Figure 1: Primary outcome by assigned antiviral (AVS-ITT).

Age

The following presents the primary outcome rate by age in years.

Figure 2: Relationship (logistic regression linear in age) between age at entry and the primary outcome.

Sex

Figure 3: Primary outcome by sex

Oxygen requirement

Figure 4: Primary outcome by supplemental oxygen

?(caption)

Oxygen requirement Total No Yes Unknown
No 917 872 (97) 31 (3) 14 (3)
Yes 646 577 (91) 60 (9) 9 (9)
(Missing) 25 25 (100) 0 (0) 0 (0)

Country

The following presents the primary outcome rate by country.

Figure 5: Primary outcome by country.

Figure 6: Primary outcome by country.

Site

The following presents the primary outcome rate by study site.

Figure 7: Primary outcome by site within country.

Figure 8: Primary outcome by site within country.

Calendar Time

Figure 9: Relationship between calendar date and the primary outcome.

There was interest in investigating a cut-point of calendar time due to changes in the predominant circulating variant. A proposed cut-point was 2021-12-20.

Figure 10: Relationship between calendar date and the primary outcome by cut-point, FAS-ITT.

Figure 11: Relationship between calendar date and the primary outcome by cut-point, AVS-ITT.

Baseline CRP

Baseline CRP Total No Yes Unknown
[3,41] 47 45 (96) 2 (4) 0 (4)
(41,81] 46 39 (85) 7 (15) 0 (15)
(81,467] 46 43 (93) 3 (7) 0 (7)
(Missing) 16 16 (100) 0 (0) 0 (0)
Table 9: Relationship between CRP and primary outcome, AVS-ITT.

Days since symptom onset

Figure 12: Relationship (logistic regression linear) between days since symptom onset at entry and the primary outcome.

MLE Estimates

As a point of reference, treatment only logistic regression models are estimated using maximum likelihood for each of the 3 analysis sets. These are obviously inappropriate given the design, but provide some reference values.

FAS-ITT

effect group term estimate std.error statistic p.value conf.low conf.high
fixed NA (Intercept) 0.03 0.03 -3.78 0.00 0.00 0.18
fixed NA facAA0 0.74 0.66 -0.34 0.73 0.13 4.26
fixed NA facAA2 0.39 0.26 -1.43 0.15 0.11 1.42
fixed NA facCC0 1.95 1.39 0.94 0.35 0.48 7.89
fixed NA facCC2 0.75 0.20 -1.07 0.28 0.44 1.27
fixed NA facCC3 0.97 0.31 -0.09 0.92 0.52 1.82
fixed NA facCC4 2.68 1.45 1.83 0.07 0.93 7.72
fixed NA inelgc3 1.76 0.95 1.04 0.30 0.61 5.07
fixed NA agegte60 1.85 0.43 2.65 0.01 1.17 2.90
fixed NA supp_oxy2 2.78 0.67 4.27 0.00 1.74 4.45
fixed NA ctryAU/NZ 1.64 1.29 0.63 0.53 0.35 7.64
fixed NA ctryNP 2.05 1.04 1.42 0.16 0.76 5.52
ran_pars epoch sd__(Intercept) 0.70 NA NA NA NA NA
Table 10: Maximum likelihood odds ratio estimates for FAS-ITT set.

ACS-ITT

effect group term estimate std.error statistic p.value conf.low conf.high
fixed NA (Intercept) 0.06 0.07 -2.42 0.02 0.01 0.58
fixed NA facAA0 0.33 0.37 -0.98 0.33 0.04 3.02
fixed NA facAA2 0.20 0.17 -1.90 0.06 0.04 1.05
fixed NA facCC2 0.74 0.20 -1.10 0.27 0.43 1.27
fixed NA facCC3 1.00 0.32 -0.01 0.99 0.53 1.87
fixed NA facCC4 2.95 1.64 1.94 0.05 0.99 8.79
fixed NA inelgc3 2.01 1.10 1.27 0.20 0.69 5.89
fixed NA agegte60 1.90 0.45 2.71 0.01 1.19 3.01
fixed NA supp_oxy2 2.97 0.72 4.45 0.00 1.84 4.79
fixed NA ctryAU/NZ 0.93 0.97 -0.07 0.94 0.12 7.26
fixed NA ctryNP 2.17 1.13 1.49 0.14 0.78 6.02
ran_pars epoch sd__(Intercept) 0.68 NA NA NA NA NA
Table 11: Maximum likelihood odds ratio estimates for ACS-ITT set.

AVS-ITT

term estimate std.error statistic p.value conf.low conf.high
(Intercept) 0.03 1.03 -3.29 0.00 0.00 0.16
facAA2 0.37 0.64 -1.53 0.13 0.10 1.26
supp_oxy2 4.96 1.07 1.50 0.13 0.91 92.60
Table 12: Maximum likelihood odds ratio estimates for AVS-ITT set.

Analyses

The SAP specified the primary analyses as using the AVS-ITT set with terms for:

  • all treatments (including ineligibilities and not-randomised terms)
  • region
  • site
  • epoch
  • age
  • sex
  • oxygen requirement
  • C-reactive protein.

This was to be repeated for FAS-ITT.

Some general notes:

  • there were concerns with the accuracy of C-reactive protein values reported in India (incorrect units reported, unrealistic values), therefore CRP is treated as unknown for Indian participants (most participants). Therefore, CRP is included for models using AVS-ITT but excluded for models using FAS-ITT.
  • all interventions in AVS-ITT were concurrently randomised. Therefore, epoch is excluded from the AVS-ITT model.
  • due to insufficient data, there are concerns that too many model parameters are included when restricting to AVS-ITT. The model parameters will be largely driven by the pre-specified priors for many of the adjustment variables. Therefore, an antiviral-treatment only model was also investigated
  • to assess prior sensitivity analyses are repeated with diffuse and sceptical priors on treatment variances, and assuming treatment coding on the effect terms rather than orthonormal coding.

FAS-ITT

Pre-specified prior

Using FAS-ITT (excluding participants with missing primary outcome) and the pre-specified primary model (excluding baseline CRP) the conditional odds ratio for Nafamostat versus standard of care was [median (95% CrI), Pr(OR<1)] 0.36 (0.10, 1.26), 0.95.

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.36 (0.10, 1.26) 0.44 (0.31) 0.95
Intermediate-dose 0.70 (0.41, 1.22) 0.73 (0.21) 0.90
Low-dose with aspirin 0.85 (0.46, 1.57) 0.89 (0.29) 0.69
Therapeutic-dose 2.60 (0.92, 7.15) 2.97 (1.64) 0.04
Ineligible aspirin 2.28 (0.61, 7.39) 2.73 (1.82) 0.10
Age ≥ 60 1.73 (1.06, 2.79) 1.79 (0.45) 0.01
Female 0.64 (0.38, 1.03) 0.65 (0.16) 0.97
Oxygen requirement 3.67 (2.22, 6.19) 3.80 (1.01) 0.00
Australia/New Zealand 1.01 (0.25, 3.94) 1.29 (1.10) 0.49
Nepal 1.60 (0.41, 5.55) 1.96 (1.41) 0.24
Posterior summaries for model parameters.
Intervention Posterior Superior Pr(OR = min(OR)) Effective Pr(OR < 1) Futile Pr(OR > 1/1.1) Equivalent Pr(1/1.1 < OR < 1.1)
Antiviral
SoC 1.00 0.05 - - -
Nafamostat 0.36 (0.10, 1.26) 0.95 0.95 0.07 0.03
Anticoagulation
Low-dose 1.00 0.06 - - -
Intermediate-dose 0.70 (0.41, 1.22) 0.67 0.90 0.18 0.13
Low-dose with aspirin 0.85 (0.46, 1.57) 0.26 0.69 0.42 0.21
Therapeutic-dose 2.60 (0.92, 7.15) 0.01 0.04 0.98 0.03
Table 13: Decision quantity summaries, FAS-ITT.

Figure 13: Posterior densities for odds ratio contrasts.

# A tibble: 57 × 10
   variable   mean median    sd   mad     q5     q95  rhat ess_bulk ess_tail
   <chr>     <num>  <num> <num> <num>  <num>   <num> <num>    <num>    <num>
 1 beta[1]  -4.32  -4.30  0.716 0.694 -5.55  -3.19    1.00    9366.   12454.
 2 beta[2]  -0.149 -0.148 0.647 0.648 -1.22   0.915   1.00   19916.   15454.
 3 beta[3]  -0.727 -0.724 0.458 0.452 -1.49   0.0100  1.00   25302.   13805.
 4 beta[4]   0.505  0.506 0.634 0.624 -0.542  1.52    1.00   24357.   13132.
 5 beta[5]   0.807  0.810 0.414 0.415  0.126  1.49    1.00   19073.   15997.
 6 beta[6]  -0.127 -0.126 0.228 0.228 -0.505  0.244   1.00   21613.   16478.
 7 beta[7]  -0.586 -0.587 0.272 0.273 -1.03  -0.136   1.00   21480.   16219.
 8 beta[8]   0.809  0.823 0.637 0.633 -0.276  1.82    1.00   28130.   14756.
 9 beta[9]   0.550  0.550 0.247 0.248  0.143  0.950   1.00   28955.   14929.
10 beta[10] -0.455 -0.452 0.250 0.248 -0.869 -0.0486  1.00   28744.   14572.
# ℹ 47 more rows
$num_divergent
[1] 0 0 0 0 2 0 0 0

$num_max_treedepth
[1] 0 0 0 0 0 0 0 0

$ebfmi
[1] 0.7739 0.7639 0.8465 0.7926 0.7714 0.7434 0.7982 0.8066

Posterior Predictive Checks

Treatment only

In this model, we investigate Nafamostat as the only fixed covariate, but still include site (not nested within region) and epoch as random effects.

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.37 (0.10, 1.23) 0.45 (0.30) 0.95
Intermediate-dose 0.74 (0.43, 1.27) 0.77 (0.22) 0.86
Low-dose with aspirin 0.84 (0.46, 1.54) 0.88 (0.28) 0.71
Therapeutic-dose 2.54 (0.88, 6.77) 2.87 (1.57) 0.04
Posterior summaries for model parameters.

Treatment coding prior

The primary model is re-fit assuming a prior specified on the treatment indicator variables rather than on the orthonormal terms. Note that the prior scales need to be adjusted. The prior \(\text{Normal}(0,1)\) on the orthonormal terms imply \(\text{Normal}(0,2)\) on the pair-wise differences. Therefore, for the treatment coding we specify a prior standard deviation of \(\sqrt{2}\) instead of 1.

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.36 (0.10, 1.21) 0.44 (0.31) 0.95
Intermediate-dose 0.66 (0.38, 1.15) 0.69 (0.20) 0.93
Low-dose with aspirin 0.80 (0.42, 1.50) 0.84 (0.28) 0.76
Therapeutic-dose 2.63 (0.89, 7.37) 3.02 (1.73) 0.04
Ineligible aspirin 2.23 (0.59, 7.21) 2.67 (1.79) 0.11
Age ≥ 60 1.74 (1.07, 2.81) 1.79 (0.45) 0.01
Female 0.63 (0.38, 1.02) 0.65 (0.17) 0.97
Oxygen requirement 3.69 (2.22, 6.24) 3.82 (1.03) 0.00
Australia/New Zealand 1.09 (0.25, 4.52) 1.41 (1.18) 0.45
Nepal 1.55 (0.39, 5.46) 1.90 (1.41) 0.26
Posterior summaries for model parameters.

Diffuse prior

For all fixed model parameters (including treatment differences), assume \(\text{Normal}(0, 10^2)\).

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.26 (0.05, 1.09) 0.34 (0.28) 0.97
Intermediate-dose 0.69 (0.38, 1.22) 0.72 (0.22) 0.89
Low-dose with aspirin 0.80 (0.41, 1.54) 0.85 (0.29) 0.75
Therapeutic-dose 3.30 (1.00, 10.34) 3.91 (2.55) 0.03
Ineligible aspirin 2.25 (0.59, 7.54) 2.70 (1.85) 0.11
Age ≥ 60 1.78 (1.08, 2.94) 1.84 (0.47) 0.01
Female 0.62 (0.37, 1.02) 0.64 (0.17) 0.97
Oxygen requirement 3.82 (2.27, 6.55) 3.97 (1.10) 0.00
Australia/New Zealand 1.85 (0.12, 25.59) 4.70 (13.95) 0.32
Nepal 3.19 (0.36, 40.93) 9.62 (89.15) 0.14
Posterior summaries for model parameters.

Sceptical prior

For treatment differences, assume \(\text{Normal}(0, 0.4^2)\)

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.74 (0.38, 1.46) 0.79 (0.28) 0.80
Intermediate-dose 0.79 (0.50, 1.24) 0.81 (0.19) 0.84
Low-dose with aspirin 0.94 (0.57, 1.53) 0.97 (0.25) 0.60
Therapeutic-dose 1.25 (0.67, 2.31) 1.31 (0.42) 0.24
Ineligible aspirin 2.37 (0.64, 7.44) 2.81 (1.85) 0.09
Age ≥ 60 1.75 (1.09, 2.80) 1.80 (0.44) 0.01
Female 0.67 (0.40, 1.07) 0.68 (0.17) 0.95
Oxygen requirement 3.59 (2.14, 6.04) 3.72 (1.00) 0.00
Australia/New Zealand 1.07 (0.29, 3.67) 1.30 (0.90) 0.46
Nepal 1.81 (0.45, 6.19) 2.20 (1.58) 0.18
Posterior summaries for model parameters.

Best Case

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.36 (0.10, 1.23) 0.44 (0.31) 0.95
Intermediate-dose 0.71 (0.41, 1.22) 0.74 (0.21) 0.89
Low-dose with aspirin 0.86 (0.46, 1.58) 0.90 (0.29) 0.69
Therapeutic-dose 2.65 (0.91, 7.40) 3.03 (1.71) 0.04
Ineligible aspirin 2.55 (0.68, 7.95) 3.01 (1.95) 0.08
Age ≥ 60 1.73 (1.07, 2.81) 1.78 (0.45) 0.01
Female 0.64 (0.39, 1.04) 0.66 (0.17) 0.96
Oxygen requirement 3.67 (2.23, 6.19) 3.81 (1.01) 0.00
Australia/New Zealand 0.97 (0.24, 3.84) 1.24 (0.96) 0.52
Nepal 1.62 (0.41, 5.65) 1.98 (1.43) 0.24
Posterior summaries for model parameters.

Figure 14: Posterior densities for odds ratio contrasts.

Worst Case

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.40 (0.11, 1.32) 0.48 (0.33) 0.93
Intermediate-dose 0.67 (0.41, 1.09) 0.69 (0.18) 0.95
Low-dose with aspirin 0.76 (0.42, 1.32) 0.79 (0.23) 0.83
Therapeutic-dose 1.74 (0.64, 4.51) 1.96 (1.02) 0.13
Ineligible aspirin 1.14 (0.31, 3.61) 1.35 (0.87) 0.42
Age ≥ 60 1.61 (1.04, 2.50) 1.65 (0.37) 0.02
Female 0.79 (0.52, 1.21) 0.81 (0.18) 0.86
Oxygen requirement 2.88 (1.83, 4.50) 2.95 (0.70) 0.00
Australia/New Zealand 2.01 (0.48, 7.63) 2.51 (1.90) 0.16
Nepal 1.48 (0.37, 5.24) 1.82 (1.39) 0.28
Posterior summaries for model parameters.

Figure 15: Posterior densities for odds ratio contrasts.

Australia/New Zealand Only

  • dropped region covariate
  • dropped ineligibility for aspirin covariate (4 cases)
Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.39 (0.10, 1.37) 0.48 (0.35) 0.93
Intermediate-dose 1.00 (0.24, 4.18) 1.31 (1.11) 0.50
Low-dose with aspirin 1.03 (0.11, 8.90) 1.87 (2.85) 0.49
Therapeutic-dose 1.09 (0.17, 6.55) 1.65 (1.94) 0.46
Age ≥ 60 1.30 (0.29, 5.28) 1.67 (1.39) 0.36
Female 0.67 (0.16, 2.41) 0.82 (0.61) 0.73
Oxygen requirement 1.88 (0.44, 10.02) 2.71 (3.08) 0.21
Posterior summaries for model parameters.

Figure 16: Posterior densities for odds ratio contrasts.

Country instead of region

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.34 (0.09, 1.19) 0.42 (0.30) 0.95
Intermediate-dose 0.71 (0.40, 1.24) 0.74 (0.21) 0.89
Low-dose with aspirin 0.85 (0.44, 1.60) 0.89 (0.30) 0.69
Therapeutic-dose 2.57 (0.89, 7.05) 2.93 (1.63) 0.04
Ineligible aspirin 2.30 (0.62, 7.40) 2.74 (1.82) 0.10
Age ≥ 60 1.72 (1.05, 2.78) 1.77 (0.45) 0.02
Female 0.65 (0.39, 1.05) 0.67 (0.17) 0.96
Oxygen requirement 3.71 (2.23, 6.23) 3.84 (1.03) 0.00
Australia 0.75 (0.19, 2.85) 0.94 (0.72) 0.67
Nepal 1.51 (0.40, 5.20) 1.84 (1.33) 0.26
New Zealand 1.77 (0.29, 7.94) 2.36 (2.10) 0.26
Posterior summaries for model parameters.
Intervention Posterior Superior Pr(OR = min(OR)) Effective Pr(OR < 1) Futile Pr(OR > 1/1.1) Equivalent Pr(1/1.1 < OR < 1.1)
Antiviral
SoC 1.00 0.05 - - -
Nafamostat 0.34 (0.09, 1.19) 0.95 0.95 0.06 0.03
Anticoagulation
Low-dose 1.00 0.07 - - -
Intermediate-dose 0.71 (0.40, 1.24) 0.66 0.89 0.19 0.13
Low-dose with aspirin 0.85 (0.44, 1.60) 0.27 0.69 0.42 0.21
Therapeutic-dose 2.57 (0.89, 7.05) 0.01 0.04 0.97 0.03
Table 14: Decision quantity summaries, FAS-ITT.

Figure 17: Posterior densities for odds ratio contrasts.

ACS-ITT

Pre-specified

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.24 (0.05, 1.02) 0.32 (0.28) 0.97
Intermediate-dose 0.70 (0.40, 1.20) 0.73 (0.21) 0.90
Low-dose with aspirin 0.85 (0.44, 1.59) 0.89 (0.30) 0.70
Therapeutic-dose 2.57 (0.88, 7.22) 2.95 (1.70) 0.04
Ineligible aspirin 2.54 (0.65, 8.60) 3.09 (2.16) 0.08
Age ≥ 60 1.76 (1.08, 2.89) 1.82 (0.47) 0.01
Female 0.64 (0.38, 1.05) 0.66 (0.17) 0.96
Oxygen requirement 3.77 (2.25, 6.43) 3.92 (1.08) 0.00
Australia/New Zealand 0.83 (0.18, 3.41) 1.08 (0.90) 0.60
Nepal 1.73 (0.44, 6.19) 2.13 (1.60) 0.21
Posterior summaries for model parameters.
Intervention Posterior Superior Pr(OR = min(OR)) Effective Pr(OR < 1) Futile Pr(OR > 1/1.1) Equivalent Pr(1/1.1 < OR < 1.1)
Antiviral
SoC 1.00 0.03 - - -
Nafamostat 0.24 (0.05, 1.02) 0.97 0.97 0.04 0.02
Anticoagulation
Low-dose 1.00 0.06 - - -
Intermediate-dose 0.70 (0.40, 1.20) 0.67 0.90 0.18 0.12
Low-dose with aspirin 0.85 (0.44, 1.59) 0.26 0.70 0.42 0.21
Therapeutic-dose 2.57 (0.88, 7.22) 0.01 0.04 0.97 0.03
Table 15: Decision quantity summaries, ACS-ITT.

Figure 18: Posterior densities for odds ratio contrasts.

Diffuse

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.26 (0.05, 1.09) 0.34 (0.28) 0.97
Intermediate-dose 0.69 (0.38, 1.22) 0.72 (0.22) 0.89
Low-dose with aspirin 0.80 (0.41, 1.54) 0.85 (0.29) 0.75
Therapeutic-dose 3.30 (1.00, 10.34) 3.91 (2.55) 0.03
Ineligible aspirin 2.25 (0.59, 7.54) 2.70 (1.85) 0.11
Age ≥ 60 1.78 (1.08, 2.94) 1.84 (0.47) 0.01
Female 0.62 (0.37, 1.02) 0.64 (0.17) 0.97
Oxygen requirement 3.82 (2.27, 6.55) 3.97 (1.10) 0.00
Australia/New Zealand 1.85 (0.12, 25.59) 4.70 (13.95) 0.32
Nepal 3.19 (0.36, 40.93) 9.62 (89.15) 0.14
Posterior summaries for model parameters.

AVS-ITT

Treatment Only

The SAP suggests that the primary analysis be based on the AVS-ITT set, but that adjustment should still be made for all the covariates. This is somewhat problematic as there is no longer sufficient data to inform all of the covariates (e.g. little information available on the effect of anticoagulation interventions, country, age etc.). The following analysis is restricted to the AVS-ITT set but restricts the analysis to a reduced set:

  • antiviral intervention
  • anticoagulation intervention
  • age group
  • oxygen requirement
Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.48 (0.15, 1.42) 0.56 (0.34) 0.91
Posterior summaries for model parameters.

Figure 19: Posterior densities for odds ratio contrasts.

Pre-specified - without site

In this section the pre-specified model with covariates is fit. However, again with no region, epoch or site specific terms.

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.40 (0.12, 1.34) 0.48 (0.32) 0.93
Intermediate-dose 0.61 (0.14, 2.51) 0.79 (0.64) 0.76
Low-dose with aspirin 0.52 (0.07, 3.44) 0.83 (0.98) 0.75
Therapeutic-dose 0.83 (0.13, 4.60) 1.22 (1.26) 0.58
Age ≥ 60 1.21 (0.30, 4.44) 1.51 (1.14) 0.39
Female 0.65 (0.16, 2.30) 0.79 (0.58) 0.75
Required oxygen 2.67 (0.59, 16.97) 4.16 (5.52) 0.11
CRP (2nd tertile) 3.15 (0.74, 15.08) 4.36 (4.25) 0.06
CRP (3rd tertile) 0.85 (0.14, 4.75) 1.25 (1.39) 0.58
CRP (unknown) 0.18 (0.00, 2.77) 0.48 (1.11) 0.88
Posterior summaries for model parameters.
Intervention Posterior Superior Pr(OR = min(OR)) Effective Pr(OR < 1) Futile Pr(OR > 1/1.1) Equivalent Pr(1/1.1 < OR < 1.1)
Antiviral
SoC 1.00 0.07 - - -
Nafamostat 0.40 (0.12, 1.34) 0.93 0.93 0.09 0.04
Table 16: Decision quantity summaries, AVS-ITT.

Figure 20: Posterior densities for odds ratio contrasts.

Pre-specified - with site

In this section the pre-specified model with covariates is fit. Again with no epoch terms, but we do include region and site.

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.36 (0.09, 1.28) 0.44 (0.32) 0.94
Intermediate-dose 0.62 (0.13, 2.84) 0.84 (0.79) 0.73
Low-dose with aspirin 0.67 (0.08, 5.28) 1.16 (1.72) 0.65
Therapeutic-dose 0.78 (0.12, 4.67) 1.19 (1.36) 0.61
Age ≥ 60 1.24 (0.27, 5.01) 1.60 (1.34) 0.39
Female 0.61 (0.13, 2.38) 0.78 (0.62) 0.75
Required oxygen 2.85 (0.57, 19.79) 4.68 (8.46) 0.10
CRP (2nd tertile) 2.90 (0.58, 15.39) 4.18 (4.60) 0.10
CRP (3rd tertile) 0.85 (0.13, 5.07) 1.30 (1.57) 0.57
CRP (unknown) 0.18 (0.00, 3.83) 0.61 (1.85) 0.85
Nepal 0.80 (0.12, 5.16) 1.25 (1.52) 0.60
Posterior summaries for model parameters.
Intervention Posterior Superior Pr(OR = min(OR)) Effective Pr(OR < 1) Futile Pr(OR > 1/1.1) Equivalent Pr(1/1.1 < OR < 1.1)
Antiviral
SoC 1.00 0.06 - - -
Nafamostat 0.36 (0.09, 1.28) 0.94 0.94 0.08 0.03
Table 17: Decision quantity summaries, AVS-ITT.

Figure 21: Posterior densities for odds ratio contrasts.

Treatment coding

Diffuse prior

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.30 (0.07, 1.14) 0.38 (0.30) 0.96
Age ≥ 60 1.11 (0.25, 4.36) 1.41 (1.12) 0.44
Female 0.65 (0.14, 2.52) 0.82 (0.64) 0.73
Required oxygen 5.30 (0.75, 120.03) 29.42 (432.34) 0.05
CRP (2nd tertile) 4.10 (0.79, 33.57) 7.23 (11.86) 0.05
CRP (3rd tertile) 1.16 (0.16, 10.48) 2.20 (3.91) 0.44
CRP (unknown) 0.00 (0.00, 2.36) 0.28 (1.73) 0.94
Posterior summaries for model parameters, AVS-ITT.

Sceptical prior

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.62 (0.27, 1.42) 0.68 (0.30) 0.87
Age ≥ 60 1.15 (0.29, 4.00) 1.40 (1.01) 0.42
Female 0.70 (0.18, 2.38) 0.85 (0.60) 0.71
Required oxygen 2.47 (0.56, 16.85) 3.99 (5.85) 0.12
CRP (2nd tertile) 3.06 (0.71, 14.54) 4.20 (4.10) 0.07
CRP (3rd tertile) 1.03 (0.18, 5.69) 1.51 (1.66) 0.48
CRP (unknown) 0.18 (0.00, 3.11) 0.51 (0.96) 0.86
Posterior summaries for model parameters, AVS-ITT.

FAS-PP

Here the primary model is fit to the FAS-PP where per-protocol participants were identified as per the provided listings. Participants may be excluded due to failing the per-protocol criteria for the anticoagulation domain or the antiviral domain (or both).

n (\%) Not randomised
to anticoagulation
Low
dose
Intermediate
dose
Low dose
with aspirin
Therapeutic
dose
Overall
Randomised 26 595 596 274 44 1535
Outcome missing 0 (0.0) 12 (2.0) 7 (1.2) 3 (1.1) 0 (0.0) 22 (1.4)
Outcome observed 26 (100.0) 583 (98.0) 589 (98.8) 271 (98.9) 44 (100.0) 1513 (98.6)
Met primary outcome 2 (7.7) 35 (6.0) 25 (4.2) 19 (7.0) 6 (13.6) 87 (5.8)
Table 18: Primary outcome by anti-coagulation intervention.
n (\%) Not randomised
to antiviral
Standard
of care
Nafamostat
Overall
Randomised 1409 67 59 1535
Outcome missing 22 (1.6) 0 (0.0) 0 (0.0) 22 (1.4)
Outcome observed 1387 (98.4) 67 (100.0) 59 (100.0) 1513 (98.6)
Met primary outcome 78 (5.6) 8 (11.9) 1 (1.7) 87 (5.8)
Table 19: Primary outcome by anti-viral intervention.
Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.15 (0.03, 0.64) 0.20 (0.17) 1.00
Intermediate-dose 0.71 (0.40, 1.23) 0.74 (0.22) 0.89
Low-dose with aspirin 0.81 (0.43, 1.53) 0.85 (0.28) 0.74
Therapeutic-dose 2.56 (0.82, 7.32) 2.94 (1.73) 0.05
Ineligible aspirin 2.27 (0.61, 7.54) 2.73 (1.84) 0.10
Age ≥ 60 1.72 (1.04, 2.83) 1.78 (0.46) 0.02
Female 0.57 (0.33, 0.95) 0.59 (0.16) 0.98
Oxygen requirement 3.84 (2.28, 6.53) 3.98 (1.10) 0.00
Australia/New Zealand 0.94 (0.22, 3.73) 1.20 (0.95) 0.53
Nepal 1.62 (0.39, 5.86) 2.00 (1.48) 0.24
Posterior summaries for model parameters.

Figure 22: Posterior densities for odds ratio contrasts.

ACS-PP

Note that for ACS-PP only participants who were not per-protocol according to the anticoagulation domain are excluded. A participant who was not per-protocol according to the antiviral domain but was per-protocol according to the anticoagulation domain is kept in the analysis set. The alternative would be to exclude both (as for FAS-PP).

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.21 (0.04, 0.89) 0.27 (0.24) 0.98
Intermediate-dose 0.69 (0.39, 1.20) 0.72 (0.21) 0.91
Low-dose with aspirin 0.82 (0.43, 1.53) 0.86 (0.29) 0.73
Therapeutic-dose 3.01 (1.01, 8.82) 3.50 (2.06) 0.02
Ineligible aspirin 2.52 (0.63, 8.33) 3.03 (2.05) 0.09
Age ≥ 60 1.76 (1.07, 2.86) 1.81 (0.46) 0.01
Female 0.61 (0.36, 1.01) 0.63 (0.17) 0.97
Oxygen requirement 3.79 (2.28, 6.44) 3.94 (1.08) 0.00
Australia/New Zealand 0.87 (0.19, 3.57) 1.13 (0.95) 0.57
Nepal 1.62 (0.40, 5.88) 2.00 (1.48) 0.24
Posterior summaries for model parameters.

Figure 23: Posterior densities for odds ratio contrasts.

AVS-PP

Note that for AVS-PP only participants who were not per-protocol according to the antiviral domain are excluded. A participant was not per-protocol according to the anticoagulation domain but was per-protocol according to the antiviral domain is kept in the analysis set. The alternative would be to exclude both (as for FAS-PP).

n (\%) Not randomised
to anticoagulation
Low
dose
Intermediate
dose
Low dose
with aspirin
Therapeutic
dose
Overall
Randomised 28 43 44 7 13 135
Outcome missing 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Outcome observed 28 (100.0) 43 (100.0) 44 (100.0) 7 (100.0) 13 (100.0) 135 (100.0)
Met primary outcome 2 (7.1) 4 (9.3) 3 (6.8) 0 (0.0) 0 (0.0) 9 (6.7)
Table 20: Primary outcome by anti-coagulation intervention, AVS-PP.
n (\%) Standard
of care
Nafamostat
Overall
Randomised 72 63 135
Outcome missing 0 (0.0) 0 (0.0) 0 (0.0)
Outcome observed 72 (100.0) 63 (100.0) 135 (100.0)
Met primary outcome 8 (11.1) 1 (1.6) 9 (6.7)
Table 21: Primary outcome by anti-viral intervention.

Pre-specified

In this section the pre-specified model with covariates is fit. However, again with no region, epoch or site specific terms.

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.15 (0.03, 0.63) 0.19 (0.17) 0.99
Intermediate-dose 0.85 (0.15, 4.59) 1.24 (1.35) 0.57
Low-dose with aspirin 0.60 (0.06, 5.38) 1.13 (1.81) 0.67
Therapeutic-dose 0.52 (0.06, 4.01) 0.89 (1.20) 0.73
Age ≥ 60 0.98 (0.17, 4.99) 1.38 (1.43) 0.51
Female 0.22 (0.03, 1.23) 0.33 (0.34) 0.96
Required oxygen 7.26 (1.04, 78.50) 15.31 (32.30) 0.02
CRP (2nd tertile) 1.19 (0.17, 7.74) 1.86 (2.26) 0.43
CRP (3rd tertile) 0.83 (0.12, 5.47) 1.32 (1.63) 0.58
CRP (unknown) 0.21 (0.00, 4.90) 0.74 (1.88) 0.82
Nepal 0.81 (0.12, 5.20) 1.27 (1.54) 0.59
Posterior summaries for model parameters.
Intervention Posterior Superior Pr(OR = min(OR)) Effective Pr(OR < 1) Futile Pr(OR > 1/1.1) Equivalent Pr(1/1.1 < OR < 1.1)
Antiviral
SoC 1.00 0.01 - - -
Nafamostat 0.15 (0.03, 0.63) 0.99 0.99 0.01 0.00
Table 22: Decision quantity summaries, AVS-PP.

Figure 24: Posterior densities for odds ratio contrasts.

Treatment Only

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.25 (0.05, 0.91) 0.31 (0.24) 0.98
Posterior summaries for model parameters.

Figure 25: Posterior densities for odds ratio contrasts.

Treatment coding

Sceptical

Parameter Median 95% CrI Mean (SD) Pr(OR < 1)
Nafamostat 0.47 (0.19, 1.14) 0.52 (0.25) 0.95
Intermediate-dose 0.92 (0.35, 2.42) 1.04 (0.54) 0.57
Low-dose with aspirin 0.89 (0.31, 2.51) 1.02 (0.59) 0.59
Therapeutic-dose 0.83 (0.30, 2.27) 0.94 (0.53) 0.65
Age ≥ 60 1.07 (0.19, 5.21) 1.48 (1.47) 0.47
Female 0.29 (0.04, 1.46) 0.41 (0.40) 0.93
Required oxygen 6.55 (0.95, 71.10) 13.78 (32.04) 0.03
CRP (2nd tertile) 1.13 (0.19, 7.00) 1.74 (2.08) 0.45
CRP (3rd tertile) 0.89 (0.14, 5.50) 1.38 (1.68) 0.55
CRP (unknown) 0.17 (0.00, 3.31) 0.55 (1.47) 0.87
Nepal 0.82 (0.13, 5.19) 1.28 (1.55) 0.58
Posterior summaries for model parameters.
Intervention Posterior Superior Pr(OR = min(OR)) Effective Pr(OR < 1) Futile Pr(OR > 1/1.1) Equivalent Pr(1/1.1 < OR < 1.1)
Antiviral
SoC 1.00 0.05 - - -
Nafamostat 0.47 (0.19, 1.14) 0.95 0.95 0.07 0.04
Table 23: Decision quantity summaries, AVS-PP.

Figure 26: Posterior densities for odds ratio contrasts.

Concurrent